Autoimmune hemolytic anemia (AIHA) is an autoimmune disease in which antibodies against the patients own red blood cells (RBC's) lead to their premature destruction (Ware et al., Autoimmune Hemolytic Anemia. In: David G Nathan, Stuart H Orkin, ed. Hematology of Infancy and Childhood (5th ed). Philadelphia: W. B. Saunders; 1998:499–522, incorporated by reference herein in its entirety). Anemia can be sudden and life threatening, or more gradual in onset. Though most cases are idiopathic, association with other forms of autoimmunity, malignancy, or infection is common (Ware et al., ibid.; Schreiber J Rheumatol. 7:395–397 (1980); Diehl et al., Semin Oncol. 25:80–97 (1998); Saif, AIDS Patient Care STDS. 15:217–224 (2001)). AIHA occurs in both children and adults, with a wide age distribution.
AIHA can be mediated by IgG, IgM, or, rarely, IgA antibodies (Ware et al., supra). Most clinically significant cases, however, are caused by IgG antibodies (Ware et al., supra; NIH conference. Pathophysiology of immune hemolytic anemia. Ann Intern Med. 87:210–222 (1977); Hashimoto, Clin Rev Allergy Immunol. 16:285–295 (1998)). In these patients, autoantibodies bind to RBC's and lead to their uptake by splenic and hepatic macrophages via Fc receptors (Izui et al., J Exp Med. 173:15–30 (1994)). Though IgG antibodies can fix complement, the principle means of destruction of RBC's in these cases is via phagocytosis (Ware et al., supra; Fossati-Jimack et al., J Exp Med. 191:1293–1302 (2000); Fossati-Jimack et al., J Exp Med. 190:1689–1696 (1999)). Therefore, even though B-cells (often with T-cell help) are producing the offending autoantibody, macrophages are essential effector cells for the development of anemia. This fact is reflected in therapy for AIHA. Splenectomy and corticosteroids, mainstays of treatment, both ultimately interfere with the phagocytosis of opsonized RBC's, among other effects (Ware et al., supra; Izui et al., supra). Experimental therapy in animal models has also utilized the specific blocking of Fc-mediated uptake of RBC's by either genetic means or the use of anti-Fc antibodies (Hazenbos et al., Immunity 5:181–188 (1996); Hazenbos et al., J Immunol. 161:3026–3032 (1998); Meyer et al., Blood 92:3997–4002 (1998); Schiller et al., Eur. J Immunol. 30:481–490 (2000); Clynes et al., Immunity 3:21–26 (1995)).
The current mainstays of standard therapy for AIHA (e.g., transfusion, corticosteroids, and, eventually, splenectomy) have many drawbacks. Transfusion have well described risks which accompany their use in AIHA patients. Corticosteroids have a multitude of well-known, undesirable acute and chronic effects. They also have another shortcoming. The onset of action of corticosteroids is variable, frequently taking many hours (or days) (Ware et al., supra). In patients who present with very severe anemia this shortcoming is a major source of concern and potential morbidity. In multiple case series, patients such as these, presenting with severe anemia (hemoglobin less than 6 g/dl), are quite common (Sokol et al., Acta Haematol. 72:245–257 (1984); Buchanan et al., J Pediatr. 88:780–783 (1976); Heisel et al., Am. J Pediatr. Hematol. Oncol. 5:147–152 (1983)).
Splenectomy, another mainstay of treatment, has many drawbacks as well. The most obvious one is routine surgical morbidity and mortality. This makes splenectomy unavailable as a therapy for certain unstable or frail patients. Another drawback of splenectomy is its association with a life-long risk of fatal sepsis from encapsulated microorganisms (Bell, Semin Hematol. 37:22–25 (2000); Hansen et al., Pediatr Dev Pathol. 4:105–121 (2001)). Finally, splenectomy does not always alleviate AIHA, because hepatic macrophages may be responsible for a significant proportion of RBC consumption (Katkhouda et al., Ann Surg. 228:568–578 (1998); Akpek et al., Am J Hematol. 61:98–102 (1999)). In fact, the substantial role of hepatic Kupffer cells in the development of AIHA has been repeatedly shown in mice (Izui et al., J Exp Med. 173:15–30 (1994); Fossati-Jimack et al., J Exp Med. 191:1293–1302 (2000); Fossati-Jimack et al., J Exp Med. 190:1689–1696 (1999); Azeredo et all, J. Exp. Med. 195:665–672 (2002). The unpredictable efficacy of splenectomy is particularly concerning in light of the short term (surgical) and life-long (infectious) morbidity of this procedure.
Therefore, there is a need in the art for safer, more effective methods for treatment of autoimmune hemolytic anemia and related diseases.